Hyaluronic acid (HA) exists as a naturally-occurring polysaccharide (also known as a mucoid polysaccharide) that can be extracted from such diverse sources as rooster comb, umbilical cord, vitreous humor, synovial fluid, pathologic joints, skin and group A and C hemolytic Streptococci. The hyaluronic acid is also defined as a high viscosity naturally occurring glycosaminoglycan having a polymeric structure containing alternating N-acetyl-D-glucosamine and D-glucuronic acid monosaccharide units linked with β 1-4 bonds and the disaccharide units linked with β 1-3 glycoside bonds. It occurs usually as the sodium salt and has a molecular weight range of about 50,000 to 8×106 Daltons.
Hyaluronic acid is a naturally occurring glycosaminoglycan. HA is ubiquitous in the organism, with the highest concentration found in soft connective tissue and joint fluid. It is a constituent of the intercellular matrix of connective tissue that exists in almost all vertebrates. It plays an important role in a number of physiological functions, including protection and lubrication of cells, maintenance of the structural integrity of tissues, transport of molecules and cells, cell migration, cell function and differentiation, and fluid retention and regulation. The clinical benefits of intra-articular HA in the horse are well published.
Natural Hyaluronic acid is polydisperse in respect of molecular weight and is known to show excellent biocompatibility even when implanted or injected into the body by virtue of the absence of species and organ specificity. However, because of the relatively short in vivo residence time of Hyaluronic acid solution in biological applications, improvements in the persistency of Hyaluronic acid by chemical crosslinking with various chemical modifiers has been attempted to broaden its use for medical materials.
The isolation and characterization of Hyaluronic acid is described in Meyer et al, J. Biol. Chem. 107, 629 (1934); J. Biol. Chem. 114, 689 (1936); Balazs, Fed. Proc. 17, 1086 (1958); Laurent et al; Biochim. Biophys. Acta 42, 476 (1960). The structure of Hyaluronic acid was elucidated by Weissman et al, J. Am. Chem. Soc. 76, 1753 (1954) and Meyer, Fed. Proc. 17, 1075 (1958).
Hyaluronic acid is an important component of the intercellular matrix. Specifically, the highest levels are found in the eye and synovial fluid of joints. In joints, its primary role is that of lubrication, reducing pain, and inflammation. In arthritic joints HA is deficient. In healthy joints, synovial fluid supplies nutrition to the articular cartilage and has incomparable functions as a lubricant and as a shock absorber. It has been determined that its excellent viscoelastisity owes heavily to one of the main components, present therein, Hyaluronic acid. Concentration and molecular weight analyses of Hyaluronic acid demonstrated the concentration and molecular weight of Hyaluronic acid in the synovial fluid from patients with arthritis such as osteoarthritis and chronic articular rheumatism generally tended to be lower than in normal synovial fluid, and the lower concentration and molecular weight of Hyaluronic acid were closely associated with development of locomotor dysfunction and pain attributable to the weaker lubricating action and the weaker protecting action on the surface of the articular cartilage of synovial fluid.
Degradation of the structures in articular cartilage is a typical characteristic of all diseases resulting in chronic destruction of the joint structures. Examples of such disorders are rheumatoid arthritis, psoriatic arthritis, and osteoarthrosis. Also, acute inflammation of a joint is often accompanied by destruction of the cartilage, although in most cases this will not develop into the chronically destructive disease. It is not known which factors are crucial for the acutely inflamed joint to either proceed to healing or develop into the chronic process. Examples of diseases involving acute joint inflammation are yersinia arthritis, pyrophosphate arthritis, gout arthritis (arthritis urica), septic arthritis and various forms of arthritis of traumatic etiology. Among other factors potentially conducive to the destruction of articular cartilage may be mentioned, for instance, treatment with cortisone; this has been known for a long time to accelerate the degenerative process in osteoarthrosis.
Such a so-called “steroid arthropathy” occurs far too often as an undesirable side effect of intra-articular cortisone treatment and can be avoided only by providing for a sufficiently long period of rest after the treatment. Steroid arthropathy is characterized by an advanced degree of articular destruction and X-ray-detectable changes of the same type as occur in advanced degenerative articular disease (Nizolek, D H & White, K K, Cornell Vet. 1981, 71:355-75). According to what is at present accepted as an explanation of the degenerative arthropathy development following treatment with cortisone, this arthropathy is believed to be caused by a primary effect on the chondrocyte metabolism. It should be noted, however, that the actual conditions prevailing in cases of arthritis with severe inflammation of the joint are of a rather more complex character, since in those cases injection of cortisone appears to have an overall positive effect on the clinical picture.
Also, it is well known that articular cartilage is composed of about 70% of water, chondrocytes and a cartilage matrix. The major components constituting the articular matrix are collagen and proteoglycan; the proteoglycan having good water retention characteristics is contained in the network of collagen having a reticulated structure. The articular matrix is rich in viscoelasticity and has an important role in reducing the stimulus and load imposed on the cartilage in order to maintain the normal morphology and function of the articular cartilage.
Osteoarthritis and rheumatoid arthritis are representative of the diseases accompanied by the destruction of the cartilage matrix. It is thought that the destruction of the matrix in these diseases is triggered by mechanical stresses with aging in the case of osteoarthritis and by excess proliferation of the surface layer cells of the synovial membrane, pannus formation and inflammatory cell infiltration in the case of rheumatoid arthritis, and both phenomena are caused through the induction of proteases. Since the degradation of articular cartilage is progressed in the extracellular region at a neutral pH, it is said that a matrix metalloprotease (hereinafter referred to as “MMP” or “MMPs” when used as the general term) whose optimal pH is in the neutral range plays a leading role in the degradation.
No medical cure exists for osteoarthritis. The progressive degeneration of the joint due to osteoarthritis is irreversible. Present therapies are directed to palliative medical therapies to reduce inflammation and pain and surgical therapies to reconstruct an affected joint or, in severe cases, to replace the joint with an artificial, prosthetic joint.
Injection of high molecular weight Hyaluronic acid solution into diseased joints has been widely adopted as an effective measure for osteoarthritis among those articular diseases, and the source of high purity HA preparations for this purpose is cockscombs. Such HA preparations from cockscombs are biologically inherent and quite safe but usually have to be administered as frequently as several to 10 times to show significant therapeutic effect. Persistency tests on rabbits revealed that HA with a molecular weight of less than 1000000 administered into the knee joint cavities disappeared from the knee joint cavities in 1 to 3 days and suggested the need of frequent administrations (Blood Coagulation and Fibrinolysis, vol, 2(1): 173-8, (1991)).
On the other hand, the molecular weight of HA found in the living body is reported to be as high as millions to 10000000, and a crosslinked HA derivative obtained by treatment with a chemical crosslinker has been developed as a therapeutic agent for knee joints with the idea that high molecular weight HA closer to the biologically intact one is likely to have higher effect. Reportedly, the crosslinked HA persisted for a period as long as 20 to 30 days after administration into rabbit knee joint cavities in the above-mentioned persistency tests and produced sufficient effect when administered three times in clinical tests, and is practically used as a therapeutic agent for arthritis (see Blood Coagulation and Fibrinolysis, ibid.; and Journal of Rheumatology vol. 25(9): 1813-9 (1998)).
A need exists for an effective palliative medication for the treatment of osteoarthritis and other joint diseases which is both safe and effective when used for both short-term and long-term therapy and which can be administered orally.